Role of Uremic Toxins in Early Vascular Ageing and Calcification

Abstract

In patients with advanced chronic kidney disease (CKD), the accumulation of uremic toxins, caused by a combination of decreased excretion secondary to reduced kidney function and increased generation secondary to aberrant expression of metabolite genes, interferes with different biological functions of cells and organs, contributing to a state of chronic inflammation and other adverse biologic effects that may cause tissue damage. Several uremic toxins have been implicated in severe vascular smooth muscle cells (VSMCs) changes and other alterations leading to vascular calcification (VC) and early vascular ageing (EVA). The above mentioned are predominant clinical features of patients with CKD, contributing to their exceptionally high cardiovascular mortality. Herein, we present an update on pathophysiological processes and mediators underlying VC and EVA induced by uremic toxins. Moreover, we discuss their clinical impact, and possible therapeutic targets aiming at preventing or ameliorating the harmful effects of uremic toxins on the vasculature.

Keywords: cardiovascular disease; chronic kidney disease; uremic toxins; vascular calcification; vascular smooth muscle cells.

Figure 1

Molecules and pathways leading to medial vascular calcification in CKD. Deteriorating renal function induced by progressing CKD leads to the accumulation of various uremic toxins including Pi, IL-1β, IL-6, TNFα and disruption of Ca²⁺ homeostasis through the upregulation of PTH and FGF-23. Elevated Ca²⁺ levels induce secretion of apoptotic bodies that contribute to hydroxyapatite (HA) crystal formation. Moreover, Pi induces the upregulation of several osteoblast-like transition molecules like BMP2, MSX2 and OPN that initiate the pro-calcifying trans-differentiation of VSMCs. IS stimulates TGFβ expression and medial layer hyperplasia. Uremic toxins such as Pi, IS or pro-inflammatory cytokines acting on endothelial cells induce vasoconstriction, upregulation of extracellular matrix degradation molecules MMP-2 and -9 and oxidative stress. ROS produced by dysregulated endothelial cells and mitochondria of activated VSMCs and cytokine recognition signaling collectively activate NF-kB liberation from its inhibitor and subsequent translocation to the nucleus where it promotes the expression of several pro-inflammatory, pro-apoptotic genes and extracellular matrix degradation molecules such as ALP, elastase and MMP-2 and -9. Ca²⁺ and Pi deposition in the form of HA crystals induces medial VC. Abbreviations: CKD: chronic kidney disease; FGF-23: fibroblast growth factor-23; PTH: parathyroid hormone; VC: vascular calcification; MMPs: matrix metalloproteinases; HA: hydroxyapatite crystal; IS: indoxyl-sulfate; VSMCs: vascular smooth muscle cell; Pi: inorganic phosphate; Ca²⁺: calcium ions; IL: interleukin; TNFα: tumor necrosis factor alpha; TGFβ: transforming growth factor beta; RANKL: receptor activator of nuclear factor kappa-Β ligand; ROS: reactive oxygen species; NF-kB: nuclear factor kappa-Β; RUNX2: Runt-related transcription factor 2; MSX2: Msh homeobox 2 protein; BMP2: bone morphogenetic protein 2; ALP: alkaline phosphatase.

Figure 2

Possible therapeutic strategies for vascular calcification in CKD. Abbreviations: CKD-MBD: Chronic kidney disease-mineral and bone disorders; RAAS: Renin-angiotensin-aldosterone system; SGLT-2: Sodium-glucose cotransporter-2 SBI-425: 5-chloro-2-methoxyphenyl-sulfonamido-nicotinamide.